Immune checkpoint inhibitor-based immunotherapy has been the most promising method for treating cancer patients. In this study, an anti-programmed death ligand 1 peptide inhibitor (APP) was engineered to act in the inner core of unimolecular polymers (Dex-PCR780-b-P(DPA-co-APP). The APP polymers had the capability of forming nano-micelles (PCR780-APP NMs) via self-assembly and featured controlled exposure in an acidic microenvironment while maintaining APP original bioactivity. Notably, in an acid tumor microenvironment, the PCR780-APP NMs (~ 121.1 nm, 2.3 mV) quickly switched into ultrasmall and positively charged PCR780-APP unimolecular micelles (PCR780-APP UMs; ~ 24.1 nm, 19.6 mV) with ultrastability, a narrow polydispersity index, and great fluorescence/photoacoustic (FL/PA) linearity due to its unique and definite unimolecular structure. Based on these advantages, under FL/PA imaging guidance, size-charge switchable PCR780-APP NMs could control exposure of APP and when combined with ultrasound, induce specific-dosage reactive oxygen species (ROS) that facilitates abundant immune T-cell recruitment and activation in deep solid tumors.

基于免疫检查点抑制剂的免疫疗法一直是治疗癌症患者最有希望的方法。在这项研究中，设计了一种抗程序性死亡配体 1 肽抑制剂 (APP)，使其作用于单分子聚合物 (Dex-PCR780- b -P(DPA- co -APP) 的内核。通过形成纳米胶束（PCR780-APP NMs）在酸性微环境中进行自组装和受控暴露，同时保持 APP 原始生物活性。值得注意的是，在酸性肿瘤微环境中，PCR780-APP NMs (~ 121.1 nm, 2.3 mV) 迅速转变为超小且带正电荷的 PCR780-APP 单分子胶束 (PCR780-APP UMs; ~ 24.1 nm, 19.6 mV)，具有超稳定性，由于其独特而明确的单分子结构，多分散指数窄，荧光/光声 (FL/PA) 线性度高。基于这些优势，在 FL/PA 成像引导下，大小电荷可切换的 PCR780-APP NMs 可以控制 APP 的暴露，并与超声结合时，诱导特定剂量的活性氧（ROS），促进大量免疫 T 细胞募集和在深部实体瘤中激活。